Chemo- and product-selective electrooxidation of 3-(arylthiomethyl)- Δ3-cephems

Article abstract of DOI:10.1055/s-0029-1216972

Electrolysis of 3-arylthiomethyl-Δ³-cephems possessing various substituents on the arylthio moiety undergo chemo selective and product-selective electrooxidation to give several different products. These include isomeric mixtures of the corresponding methoxylated cephems, a bis[(Δ³-cephem-3-yl)methyl]disulfide or a 3-dimethoxymethyl- Δ³-cephem. The selectivity of the oxidation is highly dependent on the nature of the substituents on the arylthio moiety which suggests that both steric and electronic effects play an important role in the electrooxidation of 3-arylthiomethyl-Δ³-cephems.

Full text of DOI:10.1055/s-0029-1216972

PAPER
3449
Chemo- and Product-selective Electrooxidation of
3-(Arylthiomethyl)-D3-cephems
Electrooxidation
o
i
f
3-(Ardylthiomethyl 3
e
)-
D
-cephe
o
Christian Amatore*b
a
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima-naka 3-1-1, Okayama 700-8530, Japan
Fax +81(86)2518079; E-mail: tanaka95@cc.okayama-u.ac.jp
b
c
d
Ecole Normale Supérieure, Département de Chimie, UMA CNRS 8640, 24, Rue Lhomond, 75231 Paris Cedex 5, France
Otsuka Chemical Co. Ltd., 463 Kagasuno, Kawauti-cho, Tokushima 771-0193, Japan
The Institute of Creative Chemistry Co., Musa 874-5, Okayama 701-2141, Japan
Received 13 April 2009; revised 2 June 2009
heteroatom-containing nucleophiles such as thiols, car-
bamates, amines and other heteroaromatic groups
(Scheme 2).4 However, the introduction of oxygen-con-
taining substituents at C-3¢ has only been achieved for a
Abstract: Electrolysis of 3-arylthiomethyl-D3-cephems possessing
various substituents on the arylthio moiety undergo chemoselective
and product-selective electrooxidation to give several different
products. These include isomeric mixtures of the corresponding
methoxylated cephems, a bis[(D3-cephem-3-yl)methyl]disulfide or few examples owing to the poor nucleophilicity of oxygen
a 3-dimethoxymethyl-D3-cephem. The selectivity of the oxidation is
highly dependent on the nature of the substituents on the arylthio
moiety which suggests that both steric and electronic effects play an
important role in the electrooxidation of 3-arylthiomethyl-D3-ceph-
ems.
nucleophiles.5,6 For example, methoxylation of 3-chlo-
romethylcephalosporin (2, GCLE®)7 in methanol at ambi-
ent temperature for two weeks gave only a 7% yield of the
desired cephalosporin 3a (Scheme 3).
In order to access efficiently cephalosporins with oxygen
substituents at C-3¢, we investigated a two-step transfor-
mation of 3-chloromethylcephalosporin 2; (1) substitution
Key words: antibiotics, chemoselective, electrooxidation, radical
cation
The electrogeneration and reactions of radical cations of
sulfides have been investigated intensively because their
unique electrochemical and chemical properties are uti-
lized in many organic transformations.1a Reactions of the
radical cations of the sulfides so far disclosed are classi-
fied into the following three categories:1 (1) oxidation at
the sulfur atom to afford a sulfoxide, a sulfone or a sulfo-
nium ion (Scheme 1, type A), (2) sulfur–carbon bond fis-
sion leading to a thiyl radical and a carbocation (type B),
and (3) a-deprotonation followed by one-electron oxida-
tion to generate a sulfenium ion which subsequently reacts
with a nucleophile to afford a-substituted products (type
C). Each type of reaction offers various applications in or-
ganic synthesis. To date, electrooxidation has only been
applied to simple sulfenyl compounds, and only a few
studies on the electrooxidation of sulfenyl compounds
bearing several electroactive functional groups have been
reported.2 Indeed, it is not easy to accomplish chemo-
selective electrooxidation of sulfide moieties without af-
fecting other electroactive functional groups.
Ar
Ar
S
R
– e–
+
S
R
– H+, – e–
YH, – e–
Y
R+
S+
Ar–S· +
S+
Ar
or
·S–R
Ar
R
Ar+
+
R'
sulfenium
Nu–
Nu
sulfonium
or
Nu–
On
(Ar–S)2 + R–Nu
S
S
Ar
R
Ar
sulfoxide (n = 1)
sulfone (n = 2)
Ar–Nu + (R–S)2
(type B)
R'
(type C)
Scheme 1 Reactions of radical cations of sulfides
amido-sub.
S
C(3')-sub.
N
O
CO2H
Cephalosporin antibiotics possessing various functional
groups at the C-3¢ position have attracted significant at-
tention as these C-3¢ substituents may play a significant
role in their antibacterial activity.3 Typically, C-3¢ substi-
tuted cephalosporins are prepared by modification of the
C-3¢ substituents of 7-aminocephalosporanic acid 1 (7-
ACA) and 3-halomethylcephalosporins on reaction with
cephalosporin antibiotics
S1
H2N
O
S1
BnCONH
7
6
7
6
2
3
2
3
4
N
5
OAc
N
5
X
O
3'
3'
CO2H
CO2PMB
X = Cl (GCLE®)
3a X = OMe
1 (7-ACA)
2
SYNTHESIS 2009, No. 20, pp 3449–3459
Advanced online publication: 28.08.2009
x
x.
x
x
.
2
0
0
9
DOI: 10.1055/s-0029-1216972; Art ID: F08009SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Examples of C-3¢ substituted cephalosporins

3450
H. Tanaka et al.
PAPER
of the chlorine atom with an arylthio group to give the cor-
responding 3-arylsulfenylmethylcephalosporin 4, and (2)
electrooxidative C–S bond fission of 4 to give a carboca-
tion and subsequent nucleophilic substitution
(Scheme 3).8 In order to achieve the desired transforma-
tion, the C-3¢ sulfenyl moiety of the cephalosporins must
undergo (1) chemoselective single-electron oxidation
without affecting the other electroactive functional
groups, and (2) C–S bond cleavage to afford the desired
carbocation. For this purpose, we examined 3,5-di-tert-
butyl-4-methoxybenzenethio-, 2,6-di-tert-butyl-4-sulfa-
nylphenyl-, and 4-methoxy-2,6-dimethylbenzenethio-
groups as electroactive sulfenyl groups.
path a
S
2
6
S
N
OMe
PMBO2C
R1
O
S
a
b
3a (Δ3), 3b (Δ2)
path b
N
Ar
S
+
S
c
PMBO2C
H
N
4
MeO
CO2PMB
OMe
R1 = BnCONH
3c
BnCONH
O
S
path c
N
X
CO2PMB 2 (X = Cl)
HS–Ar 5
OMe
7
Scheme 4 Chemo- and product-selective electrooxidation of
3-arylthiomethylcephalosporins 4
t-Bu
OR
t-Bu
BnCONH
S
Ar =
SAr
N
O
t-Bu
OMe
t-Bu
OH
t-Bu
Me
CO2PMB
4a R = Me, 4b R = H
HS
HS
HS
OMe
– e–
t-Bu
Me
S
BnCONH
O
5a
5b
5c
N
MeOH
2 weeks
7%
Me
CO2PMB
S–Ar
+
HS
OMe
HS
OMe
HS
Me
MeOH
BnCONH
O
S
Me
5d
5e
t-Bu
OMe
t-Bu
5f
N
OMe
t-Bu
CO2PMB
3a
HS
MeS
MeS
OH
t-Bu
Scheme 3 Preparation of a C-3¢ oxygenated cephalosporin 3a
5g
11
12
Herein, we describe a chemo- and product-selective elec-
trooxidation of 3-arylthiomethylcephalosporin 4 leading
to D3-cephems 3,6d bis(D3-cephem-3-ylmethyl)disulfide 6
and 3-dimethoxymethyl-D3-cephem 7,6d wherein the
product selectivity was highly dependent on the nature of
the substituents on the arylthio moiety (Scheme 4).
Figure 1 Structures of compounds 5a–g, 11 and 12
Electrooxidation of p-Methoxybenzyl 3-(3,5-Di-tert-
butyl-4-methoxyphenyl)thiomethyl-7-phenylacet-
amido-D3-cephem-4-carboxylate (4a)
Preparation of 3-Arylthiomethyl-D3-cephems 4 and
Sulfides 11 and 12
Electrolysis was carried out in a beaker-type undivided
cell fitted with two platinum electrodes (1.0 × 1.5 cm2) un-
der a constant current density (10 mA/cm2). Electrooxida-
tion of 4a in dichloromethane–methanol (14:1) containing
magnesium sulfate, 2,2,2-trifluoroethanol (TFE) and
tetra-n-butylammonium tetrafluoroborate (Bu4NBF4) at
room temperature afforded the methoxylated cepha-
losporins 3 (3a:3b:3c = 70:5:25) in 80% combined yield
together with disulfide 8 and sulfinate 9, as by-products,
in 17% and 47% yields, respectively, after passage of
5 F/mol of electricity (Scheme 5, Table 1, entry 1).
3-Arylthiomethyl-D3-cephems 4a–g were prepared in ex-
cellent yields by reaction of 3-chloromethylcephalosporin
2 with the corresponding aryl thiols 5a–g (Figure 1) in the
presence of potassium bicarbonate in aqueous acetone for
30–60 minutes under ambient conditions. 1,3-Di-tert-bu-
tyl-2-methoxy-5-(methylsulfanyl)benzene (11) and 2,6-
di-tert-butyl-4-(methylsulfanyl)phenol (12) were pre-
pared by reaction of the corresponding aryl thiols 5a and
5b with methyl iodide in N,N-dimethylformamide in the
presence of sodium hydride.
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

PAPER
Electrooxidation of 3-(Arylthiomethyl)-D3-cephems
3451
t-Bu
OMe
electrolysis of 4a was carried out in acetonitrile–methanol
(5:1), methoxylated cephalosporin 3 was obtained in only
37% yield with 3b predominating (entry 4). Electrolysis
of 4a in methanol (3.0 mL) was not complete even after
passage of 5 F/mol of electricity (entry 5); in this case sig-
nificant oxidation of methanol would occur competitive-
ly.
BnCONH
O
S
– e–
N
S
CO2PMB
t-Bu
4a
BnCONH
O
S
The effect of temperature was also influential on both the
yield and the product selectivity. When electrolysis of 4a
in dichloromethane–methanol (14:1) containing magne-
sium sulfate, 2,2,2-trifluoroethanol and tetra-n-butylam-
monium tetrafluoroborate was carried out at 0 to –5 °C
under a constant current density (10 mA/cm2), the yield of
the products 3 increased slightly to 84% and the desired
D3-isomer 3a was formed preferentially (entry 6). On the
other hand, when the electrolysis of 4a was carried out at
a much lower temperature (–20 to –25 °C) the yield of 3
decreased to 77% (entry 7).
BnCONH
S
N
OMe
N
+
O
CO2PMB
CO2PMB
MeO
3a (Δ3-isomer)
3c
3b (Δ2-isomer)
t-Bu
+
MeO
t-Bu
SO2Me
+
t-Bu
MeO
t-Bu
t-Bu
OMe
t-Bu
9
S
S
Electrooxidation of p-Methoxybenzyl 3-(3,5-Di-tert-
butyl-4-hydroxyphenyl)thiomethyl-7-phenylacet-
amido-D3-cephem-4-carboxylate (4b)
8
Scheme 5 Electrooxidation of cephem 4a
Next, the electrolysis of D3-cephem 4b was investigated
(Table 2). Electrooxidation of 4b in acetonitrile–methanol
(5:1) containing tetraethylammonium perchlorate
(Et4NClO4) at room temperature under a constant current
density (10 mA/cm2, 4 F/mol) proceeded to afford bis[(4-
p-methoxybenzyloxycarbonyl-7-phenylacetamido-D3-
cephem-3-yl)methyl] disulfide (6) and 2,6-di-tert-butyl-
4,4-dimethoxycyclohexa-2,5-dien-1-one (10) in 90% and
91% yields, respectively (entry 1). Electrolysis of 4b in
methanol containing tetraethylammonium perchlorate af-
forded a mixture of disulfide 6 (43%) and semiquinone 10
(58%) together with recovered 4b (27%) after passage of
4 F/mol of electricity (entry 2). The correct choice of sup-
porting electrolyte was also important. When the electro-
The addition of 2,2,2-trifluoroethanol was essential in or-
der to obtain the desired D3-isomer 3a predominantly; the
undesired D2-isomer 3b was obtained as the major product
in the absence of 2,2,2-trifluoroethanol (entry 2). Addition
of magnesium sulfate was also necessary for the forma-
tion of 3a, otherwise 3b was again obtained as the major
product (entry 3). It is likely that isomerization of D3-
cephem 3a into the D2-isomer 3b occurs under the influ-
ence of an electro-generated base (EG-base);9 2,2,2-tri-
fluoroethanol and magnesium sulfate probably function
as scavengers of the electro-generated base.
Correct choice of the solvent was also important for the
electrooxidative transformation of 4a into 3. When the
Table 1 Electrooxidation of p-Methoxybenzyl 3-(3,5-Di-tert-butyl-4-methoxyphenyl)thiomethyl-7-phenylacetamido-D3-cephem-4-carboxy-
late (4a)a
Entry Solvent
Additive
Electricity Temp
Yieldb (%)
MeOH
(mL)
CH2Cl2
(mL)
MeCN
(mL)
MgSO4
(mg)
TFE
(mL)
(F/mol)
(°C)
3 (3a/3b/3c)c
8
9
4ad
1
2
3
4
5
6
7
0.2
0.2
0.2
0.5
3.0
0.2
0.2
2.8
2.8
2.8
–
–
50
50
–
0.05
–
5
5
4
3
5
5
5
20–25
80 (70:5:25)
80 (19:56:25)
62 (30:62:8)
37 (16:84:<1)
17 (28:36:36)
84 (80:2:18)
77 (78:2:20)
17
14
53
62
18
9
47
60
29
16
35
78
65
8
10
4
–
20–25
20–25
20–25
20–25
0–5
–
–
2.5
–
–
–
6
–
–
–
20
nde
nde
2.8
2.8
–
50
50
0.05
0.05
–
–20 to –25
10
a Electrolysis was carried out on 4a (150 mg) containing Bu4NBF4 (50 mg) under an Ar atm.
b Isolated yield.
c Ratio determined by HPLC and 1H NMR.
d Yield of recovered 4a.
e Not detected (nd).
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

3452
H. Tanaka et al.
PAPER
Figure 2 Cyclic voltammograms of 3-arylthiomethyl-D3-cephems 4a, 4b, 4d and 4g and sulfides 11 and 12
lysis of 4b was carried out using tetra-n-butylammonium
tetrafluoroborate as the supporting electrolyte in acetoni-
trile–methanol (5:1) or dichloromethane–methanol (5:1),
both the yields of 6 and the current efficiency decreased
significantly (entries 3 and 4).
Arylthio Moiety Substituent Effect on the Electro-
oxidation of 3-Arylthiomethyl-D3-cephems 4
When the electrolysis of 3-arylthiomethyl-D3-cephems
4c–g bearing different substituents on the arylthio moi-
eties was carried out in a similar manner as described
above, significant changes in the product distributions
were observed. Electrolysis of p-methoxybenzyl 3-(2,6-
dimethyl-4-methoxyphenylthio)methyl-7-phenylacetami-
do-D3-cephem-4-carboxylate (4c) proceeded in a similar
manner to that of 4a to afford methoxylated cephalospor-
ins 3 in 62% combined yield together with a trace of the
acetal 7 (Table 3, entry 2). In contrast, the electrooxida-
tion of D3-cephem 4d proceeded in a different manner to
afford 7 predominately (entry 3). Electrolysis of D3-ceph-
ems 4e and 4f also afforded acetal 7 as the major product
(entries 4 and 5). However, electrolysis of unsubstituted
3-phenylthiomethyl-D3-cephem 4g afforded a complex
mixture containing only trace amounts of cephems 3 and
acetal 7 (entry 6).
Table 2 Electrooxidation of p-Methoxybenzyl 3-(3,5-Di-tert-butyl-
4-hydroxyphenyl)thiomethyl-7-phenylacetamido-D3-cephem-4-car-
boxylate (4b)a
t-Bu
BnCONH
S
– e–
N
S
OH
t-Bu
O
CO2PMB
4b
t-Bu
BnCONH
S
N
MeO
MeO
S
O
+
O
CO2PMB
t-Bu
10
6
2
Cyclic Voltammetry
Entry Solvent
Electrolyte
Yield (%)b
The product selectivity of the electrooxidation of 3-aryl-
thiomethyl-D3-cephems 4 appears to be highly dependent
on the nature of the substituents on the arylthio moieties.
We measured the redox potentials of 3-arylthiomethyl-D3-
cephems 4a, 4b, 4d and 4g and sulfides 11 and 12 by cy-
clic voltammetry [acetonitrile, platinum as the working
electrode, saturated calomel reference electrode (SCE)]
(Figure 2 and Table 4).
The cyclic voltammogram of D3-cephem 4a demonstrated
two irreversible oxidation peaks at +1.42 (Ox1 4a) and
+1.68 V (Ox2 4a) vs. the saturated calomel reference elec-
6
10
91
58
64
37
1
2
3
4
MeCN–MeOH (5:1)
MeOH
Et4NClO4
Et4NClO4
Bu4NBF4
Bu4NBF4
90
43
58
21
MeCN–MeOH (5:1)
CH2Cl2–MeOH (5:1)
a Electrolysis was carried out on cephem 4b (150 mg) and electrolyte
(50 mg) in an undivided cell containing two Pt electrodes (1.0 × 1.5
cm2) under a constant current density (10 mA/cm2, 4 F/mol) at r.t.
b Yield of isolated product after column chromatography.
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

PAPER
Electrooxidation of 3-(Arylthiomethyl)-D3-cephems
3453
Table 3 Electrooxidation of 3-Arylthiomethyl-D3-cephems 4a,c–ga
11 and 12 each exhibited one irreversible oxidation peak
at +1.28 (Ox1 11), and +1.03 V (Ox1 12) vs. the SCE. The
oxidation peaks Ox1 4a and Ox1 4b of 4a and 4b are compa-
rable with the oxidation peaks Ox1 11 and Ox1 12 of sulfides
11 and 12, respectively. These similarities suggest that
peaks Ox1 4a and Ox1 4b are ascribable to the one-electron
oxidation peak of the arylsulfenyl moiety on the C-3 side
chain of compounds 4a and 4b.
The cyclic voltammogram of D3-cephem 4d showed three
irreversible oxidation peaks at +1.30 (Ox1 4d), +1.45
(Ox2 4d) and +1.66 V (Ox3 4d) (Figure 2). The oxidation
peaks Ox2 4d and Ox3 4d appear to be comparable with ox-
idation peaks Ox1 4a and Ox2 4a, however, there was no ox-
idation peak corresponding to the oxidation peak Ox1 4d in
the cyclic voltammogram of 4a. This suggests that the
electrooxidation of cephem 4d occurs via a different path-
way to that of 4a. In contrast, D3-cephem 4g exhibited
only one irreversible oxidation peak at +1.71 V (Ox1 4g).
Thus, oxidation of the C-3 side chain and other electroac-
tive functional groups in 4g occurs to afford a complex
mixture of products.
Entry Ar
Yield (%)b
3
Ratio (3a/3b/3c)c
7
t-Bu
OMe
t-Bu
1
84
80:2:18
70:1:29
trace
4a
Me
OMe
2
62
trace
Me
4c
Me
Me
OMe
3
4
22
18
94:1:4
48
32
4d
4e
OMe
Me
These facts indicate that chemoselective electrooxidation
of the 3-arylthiomethyl moieties of compounds 4a, 4b and
4d occurred predominantly, and there were no appreciable
amounts of products derived from oxidation of any of the
other electroactive functional groups present on the ceph-
alosporin, that is, the acetamide, b-lactam, carboxyl and
sulfide moieties (Figure 3).
60:20:20
5
18
–
66:1:33
–
27
–
4f
Ph
6d
4g
sulfone
a Electrolysis of a soln of cephem 4 (200 mg) in CH2Cl2–MeOH (3.7
mL:0.3 mL) containing Bu4NBF4 (50 mg), MgSO4 (50 mg) and TFE
(0.05 mL) was carried out in an undivided cell containing two Pt elec-
trodes (1.0 × 1.5 cm2) under a constant current density (10 mA/cm2, 5
F/mol) at r.t.
sulfoxide
methoxylation
fission
methoxylation
BnCONH
O
S
b Yield of isolated product after column chromatography.
c Ratio determined by HPLC and 1H NMR.
N
S
Ar
d A complex mixture was obtained.
CO2PMB
fission
fission
fission
Table 4 Oxidation Potentials (V) of 3-Arylthiomethyl-D3-cephems
4a, 4b, 4d and 4g and Sulfides 11 and 12a
Figure 3 Potentially electroactive functional groups in cephems 4
Compound
Oxidation potential (V) vs. SCE
Plausible Mechanisms for the Electrooxidations of
Arylthiomethyl-D3-cephems
Ox1
Ox2
+1.68
+1.74
+1.45
–
Ox3
Plausible mechanisms for the electrooxidations of D3-
cephems 4 are shown in Schemes 6– 8. During the initial
electrooxidation stage of D3-cephems 4a, 4b and 4d, one-
electron oxidation of the sulfide moiety at C-3¢ would oc-
cur to afford the corresponding radical cation 4+. Subse-
quently, 4+ can undergo three different types of reaction.
The first type occurs during the electrolysis of D3-cephem
4b (Scheme 6). Deprotonation of the aryl hydroxy group
and single-electron oxidation would afford cationic inter-
mediate 14. Subsequent methoxylation (14→15) and a
second one-electron oxidation (15→16) followed by S–C
bond cleavage would afford radical 17 and cation 18.
Finally, thiyl radical 17 and cation 18 would give
4a
4b
4d
4g
11
12
+1.42
+1.13
+1.30
+1.71
+1.28
+1.03
–
+1.88
+1.66
–
–
–
–
–
a Reagents and conditions: analyte (0.024 mmol), Bu4NBF4 (1.5 g),
MeCN (15 mL); Pt electrode vs. SCE; scan rate = 200 mV/s.
trode. Anodic potential sweep of D3-cephem 4b gave three
oxidation peaks at +1.13 (Ox1 4b), +1.74 (Ox2 4b), and
+1.88 V (Ox3 4b). The cyclic voltammograms of sulfides
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

3454
H. Tanaka et al.
PAPER
bis(D3-cephem-3-yl)methyl disulfide 6 and semiquinone
10, respectively.
4a
– e–
BnCONH
O
S
t-Bu
OMe
t-Bu
t-Bu
OH
S
N
S
– e–
4b
S
CO2PMB
4b•+
t-Bu
t-Bu
• +
4a
S
– H+, – e–
S
O
ArS·
ArS SAr
20
8
14
t-Bu
t-Bu
S
– e–
+ MeOH
ArSO2Me
S
+
MeOH, – H+
S
O
19
9
MeO
15
t-Bu
t-Bu
+ MeOH
– H+
S
– e–
+ MeOH
S
O
– H+
BnCONH
O
S
MeO
t-Bu
16
N
OMe
BnCONH
O
S
S
S
CO2PMB
N
3a (Δ3-isomer)
S
S
CO2R2
MeO
EG Base
3c
17
t-Bu
6
2
BnCONH
S
t-Bu
MeOH
– H+
N
OMe
O
MeO
MeO
MeO
O
O
CO2PMB
3b (Δ2-isomer)
t-Bu
t-Bu
18
Scheme 7 Proposed mechanism for the electrooxidation of 4a
Scheme 6 A plausible mechanism for the electrooxidation of 4b
The difference in product selectivity leading to 3 or 7
(path b or path c) can be reasonably explained on the basis
of the bulkiness of the substituents on the aryl moiety.
Radical cation 4+ would afford the sulfenium cation 21
through deprotonation and a second one-electron oxida-
tion as described above. The most stable conformation of
the sulfenium ion 21 would involve a co-planar arrange-
ment throughout the p-conjugated system (Scheme 9).
Sulfenium ion 21¢ bearing bulky aryl substituents, e.g.,
3,5-di-tert-butyl (4a) and 2,6-dimethyl (4c) groups, would
not be able to adopt such a co-planar form and would de-
viate from the most stable arrangement. Therefore, depro-
tonation of radical cation 4+ would not occur and instead
C–S bond cleavage would take place to afford the cation
19 and the thiyl radical 20 (path b). On the other hand,
electrooxidation of cephems 4d–f bearing less-bulky aryl
substituents at C-3¢ would afford the stable sulfenium ion
21 resulting in the formation of the corresponding acetal 7
(path c).
The second type of reaction would involve C–S bond fis-
sion of 4a+ leading to cation 19 and thiyl radical 20
(Scheme 7). Cation 19 would react rapidly with methanol
to afford 3-methoxy-D3-methylcephem 3a or 4-methoxy-
3-exo-methylenecepham 3c.10 The D2-isomer 3b would be
expected to form as a secondary product via isomerization
of 3a (D3-isomer) mediated by the electro-generated base.
The thiyl radical 20 would undergo dimerization to give
disulfide 8 which, in methanol, can be partly converted
into sulfinate 9 by further electrooxidation. In fact, elec-
trolysis of isolated disulfide 8 afforded sulfinate 9 in 90%
yield [dichloromethane–methanol (10:1), magnesium sul-
fate, 2,2,2-trifluoroethanol, tetra-n-butylammonium tet-
rafluoroborate, constant current density (10 mA/cm2,
8 F/mol)].11
The third type of the reaction would occur predominantly
in the electrooxidation of 4d to afford the acetal 7
(Scheme 8). Elimination of the a-proton of radical cation
4+ followed by a further one-electron oxidation would af-
ford the corresponding sulfenium cation 21 (path c). This
cation would undergo methanolysis and further oxidative
C–S bond cleavage to afford 3-dimethoxymethyl-D3-
cephem 7 via S,O-acetal 22.
In conclusion, chemo- and product-selective electrooxi-
dation of D3-cephems 4, possessing novel arylsulfenyl
moieties, occurs at the C-3¢ position. Electrooxidation of
D3-cephems 4a,b was achieved in the presence of magne-
sium sulfate, 2,2,2-trifluoroethanol and tetra-n-butylam-
monium tetrafluoroborate in dichloromethane–methanol,
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

PAPER
Electrooxidation of 3-(Arylthiomethyl)-D3-cephems
3455
4d
– e-
the substituents on the arylsulfenyl moieties and has been
explained based on electronic and steric effects. The
3,5-di-tert-butyl-4-methoxybenzenethio and 2,6-di-tert-
butyl-4-sulfanylphenyl groups act as new and efficient
electroauxiliaries.12
S
b
S
c
Ar
H
CO2R2
4d• +
IR spectra were recorded on Jeol RFX-3002 and Jasco FT/IR-5000
spectrophotometers. H NMR spectra were recorded on a Varian
path b
path c
1
– H+
– e–
VXR-200 spectrometer (200 MHz) and 13C NMR spectra were re-
corded on a Varian Mercury 300 spectrometer (75 MHz), with
chemical shift (d) values reported in ppm. High-resolution mass
spectra were measured with a Hitachi M-80 spectrometer. Elemen-
tal analyses were recorded using a Perkin-Elmer CHNS 2400 mi-
croanalyzer. Column chromatographic purification was carried out
on Wakogel® C-200 silica gel (100–200 mesh). MeOH, CH2Cl2 and
MeCN were distilled over Mg, P2O5 and CaH2, respectively. 3-
Chloromethylcephalosporin (GCLE®, 2) was a gift from Otsuka
Chemical Co. Ltd, and was used without further purification. 4-
Methoxybenzenethiol (5e), 4-methylbenzenethiol (5f) and ben-
zenethiol (5g) were purchased from commercial sources and used
without further purification.
20
8
S
S
+
S
Ar
+
19
21
+ MeOH
+ MeOH
– H+
– e–
S
+ MeOH
S
Ar
OMe
9
22
– e–
– ArS·
+ MeOH
EG-base
3b
3,5-Di-tert-butyl-4-methoxybenzenethiol (5a); Typical Proce-
dure
To a mixture of 2,6-di-tert-butylanisole (3.1 g, 14.1 mmol) and Fe
powder (0.5 g) in MeCN (20 mL) was added a soln of S2Cl2 (1.1
mL, 13.7 mmol) in MeCN (5 mL) with stirring at ca. –20 to –30 °C.
The mixture was stirred at r.t. for 18 h and then diluted with EtOAc
(50 mL), washed with brine (3 × 10 mL), dried (Na2SO4) and con-
centrated under reduced pressure. The residue (2.9 g) was dissolved
in benzene (20 mL), treated with Zn powder (2.0 g) and 18% aq HCl
(7.0 mL) and stirred at 60 °C for 15 h. The resulting mixture was ex-
tracted with EtOAc (3 × 10 mL) and the combined extracts were
washed with brine (3 × 10 mL), dried (Na2SO4) and concentrated
under reduced pressure. The residue was distilled under reduced
pressure (135–140 °C, 3 mmHg) to afford 5a as a pale-yellow oil;
yield: 1.8 g (50%).
S
OMe
OMe
7
Scheme 8 A plausible mechanism for the electrooxidation of 4d
or tetraethylammonium perchlorate in acetonitrile–meth-
anol to afford D3-cephem 3a as the major isomeric product
(3b and 3c are formed as minor isomers) and bis[(D3-
cephem-3-yl)methyl] disulfide 6, respectively. On the
other hand, electrooxidation of D3-cephem 4d gave pre-
dominantly 3-dimethoxymethyl-D3-cephem 7. The prod-
uct selectivity was highly dependent upon the nature of
IR (neat): 2963, 2870, 2564, 2012, 1736, 1575, 1448, 1407, 1361,
1222 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.39 (s, 18 H), 3.35 (s, 1 H), 3.65
(s, 3 H), 7.18 (s, 2 H).
+
R'
R
S
S
OMe
R
R'
N
H
OR2
– H+
– e–
O
21' (R = t-Bu or R' = Me)
R
R'
R'
S
S
+
S
OMe
+
S
Ar
N
C–S bond
fission
+
CH2
CO2R2
19
N
20
H
H
R
CO2R2
+
– H+
– e–
H
•+
Me
OMe
Me
4
S
S
N
H
H
OR2
O
21 (R = Me, R' = H)
Scheme 9 Conformations of sulfenium ions 21 and 21¢
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

3456
H. Tanaka et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 31.91, 35.72, 64.27, 122.98,
J = 14 Hz, 1 H), 3.75 (s, 3 H), 4.11 (d, J = 14 Hz, 1 H), 4.82 (d, J = 5
Hz, 1 H), 4.94 (d, J = 12 Hz, 1 H), 5.03 (d, J = 12 Hz, 1 H), 5.70 (dd,
J = 9, 5 Hz, 1 H), 6.51 (d, J = 9 Hz, 1 H), 6.83 (d, J = 9 Hz, 2 H),
7.22–7.35 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 28.27, 31.95, 35.81, 38.40, 43.31,
55.12, 57.83, 58.95, 64.33, 67.55, 113.86, 123.94, 126.81, 127.07,
127.67, 128.31, 129.12, 129.42, 130.43, 130.71, 131.76, 133.71,
144.56, 159.83, 161.11, 164.41, 171.16.
128.78, 144.60, 158.25.
Anal. Calcd for C15H24OS: C, 71.38; H, 9.58. Found: C, 71.43; H,
9.51.
2,6-Di-tert-butyl-4-sulfanylphenol (5b)
2,6-Di-tert-butylphenol (3.0 g, 15 mmol) was treated with S2Cl2
(1.0 mL, 13 mmol) and Fe powder (0.5 g) in MeCN (25 mL) at r.t.
for 18 h. The residue (after work-up) was treated with Zn powder
(2.0 g) in benzene (20 mL) and 18% aq HCl (7.0 mL) at 60 °C for
10 h to afford 5b as a colorless solid; yield: 2.4 g (69%).
Anal. Calcd for C39H46N2O6S2: C, 66.64; H, 6.60; N, 3.99. Found:
C, 66.44; H, 6.65; N, 3.95.
IR (KBr): 3639, 2961, 2874, 2561, 1748, 1577, 1424, 1310, 1234
cm–1.
1H NMR (200 MHz, CDCl3): d = 1.50 (s, 18 H), 3.44 (s, 1 H), 5.24
(s, 1 H), 7.26 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 30.09, 34.29, 118.23, 128.23,
136.85, 152.77.
p-Methoxybenzyl 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)thio-
methyl-7-phenylacetamido-D3-cephem-4-carboxylate (4b)
Reaction of cephem 2 (1.0 g, 2.1 mmol), 2,6-di-tert-butyl-4-sulfa-
nylphenol (5b) (0.52 g, 2.2 mmol) and KHCO3 (0.42 g, 4.2 mmol)
in acetone (20 mL) and H2O (3 mL) afforded 4b as a colorless solid;
yield: 1.4 g (98%).
IR (KBr): 3631, 3334, 2961, 2253, 1774, 1719, 1677, 1613, 1516
cm–1.
Anal. Calcd for C14H22OS: C, 70.54; H, 9.30. Found: C, 70.28; H,
9.31.
1H NMR (200 MHz, CDCl3): d = 1.38 (s, 18 H), 3.36 (d, J = 18 Hz,
1 H), 3.59 (d, J = 18 Hz, 1 H), 3.64 (s, 2 H), 3.72 (d, J = 13 Hz, 1
H), 3.79 (s, 3 H), 4.02 (d, J = 13 Hz, 1 H), 4.86 (d, J = 5 Hz, 1 H),
4.89 (d, J = 12 Hz, 1 H), 5.03 (d, J = 12 Hz, 1 H), 5.29 (s, 1 H), 5.74
(dd, J = 9, 5 Hz, 1 H), 5.97 (d, J = 9 Hz, 1 H), 6.84 (d, J = 9 Hz, 2
H), 7.21–7.38 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 28.42, 30.14, 34.33, 39.03, 43.18,
55.17, 58.05, 59.00, 67.38, 113.81, 122.94, 123.75, 126.85, 127.45,
128.95, 129.34, 130.34, 131.25, 131.96, 133.95, 136.71, 154.35,
159.69, 161.13, 164.68, 171.28.
4-Methoxy-2,6-dimethylbenzenethiol (5c)13
3,5-Dimethylanisole (3.0 g, 22 mmol) was reacted with S2Cl2 (1.1
mL, 14 mmol) and Fe powder (0.5 g) in MeCN (15 mL) at r.t. for
12 h. The residue (after work-up) was treated with Zn powder (3.5
g) in benzene (30 mL) and 18% aq HCl (30 mL) at 60 °C for 20 h
to afford 5c as a pale-yellow oil; yield: 1.5 g (40%). Compound 5c
was used for the preparation of cephem 4c without further purifica-
tion.
IR (neat): 2938, 2835, 1597, 1472, 1317, 1163 cm–1.
Anal. Calcd for C38H44N2O6S2: C, 66.25; H, 6.44; N, 4.07. Found:
C, 66.24; H, 6.62; N, 4.00.
1H NMR (200 MHz, CDCl3): d = 2.38 (s, 6 H), 2.95 (s, 1 H), 3.76
(s, 3 H), 6.66 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 22.68, 55.23, 113.9, 122.61,
p-Methoxybenzyl 3-(2,6-Dimethyl-4-methoxyphenylthio)meth-
yl-7-phenylacetamido-D3-cephem-4-carboxylate (4c)
Reaction of 2 (1.0 g, 2.1 mmol), 4-methoxy-2,6-dimethylben-
zenethiol (5c) (0.42 g, 2.5 mmol) and KHCO3 (0.42 g, 4.2 mmol) in
acetone (10 mL) and H2O (1.5 mL) afforded 4c as a colorless solid;
yield: 1.2 g (95%).
138.98, 157.73.
4-Methoxy-3,5-dimethylbenzenethiol (5d)14
To a soln of 2,6-dimethylanisole (3.3 g, 24 mmol) in MeCN (28
mL) were added S2Cl2 (1.9 mL, 14 mmol) and Fe powder (0.5 g),
and the resulting mixture was stirred at r.t. for 12 h. The residue (af-
ter work-up) was treated with Zn powder (2.0 g) in benzene (20 mL)
and 18% aq HCl (10 mL) at 60 °C for 10 h to afford 5d as a pale-
yellow oil; yield: 2.8 g (64%). Compound 5d was used for the prep-
aration of cephem 4d without further purification.
IR (neat): 2939, 2825, 2561, 1586, 1477, 1216, 1014 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.23 (s, 6 H), 3.32 (s, 1 H), 3.69
(s, 3 H), 6.90 (s, 2 H).
IR (Nujol): 3270, 1771, 1713, 1652, 1614, 1593, 1531, 1510 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.44 (s, 6 H), 3.25 (d, J = 18 Hz,
1 H), 3.38 (d, J = 12 Hz, 1 H), 3.60 (d, J = 4 Hz, 1 H), 3.63 (d, J = 4
Hz, 1 H), 3.73 (s, 3 H), 3.76 (d, J = 18 Hz, 1 H), 3.80 (s, 3 H), 4.06
(d, J = 12 Hz, 1 H), 4.75 (d, J = 12 Hz, 1 H), 4.88 (d, J = 4 Hz, 1
H), 4.99 (d, J = 12 Hz, 1 H), 5.74 (dd, J = 8, 4 Hz, 1 H), 6.06 (d,
J = 8 Hz, 1 H), 6.63 (s, 2 H), 6.86 (d, J = 10 Hz, 2 H), 7.20–7.40 (m,
7 H).
13C NMR (75 MHz, CDCl3): d = 22.20, 28.63, 37.29, 43.19, 54.91,
55.10, 56.98, 58.78, 67.53, 113.61, 122.93, 123.08, 126.73, 127.54,
129.00, 129.29, 130.34, 133.54, 146.04, 159.47, 159.59, 161.08,
164.12, 170.93.
13C NMR (75 MHz, CDCl3): d = 15.96, 59.74, 124.34, 130.40,
131.28, 155.54.
p-Methoxybenzyl 3-(3,5-Di-tert-butyl-4-methoxyphenyl)thio-
methyl-7-phenylacetamido-D3-cephem-4-carboxylate (4a);
Typical Procedure
Anal. Calcd for C33H34N2O6S2: C, 64.06; H, 5.54; N, 4.53. Found:
C, 63.73; H, 5.51; N, 4.40.
A mixture of 3-chloromethyl-D3-cephem 2 (1.0 g, 2.1 mmol), 3,5-
di-tert-butyl-4-methoxybenzenethiol (5a) (0.60 g, 2.4 mmol) and
KHCO3 (0.44 g, 4.4 mmol) in acetone (20 mL) and H2O (3 mL) was
stirred at r.t. for 30 min. The reaction mixture was diluted with
EtOAc (50 mL), washed with brine (3 × 10 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was chromato-
graphed over silica gel (eluent: toluene–EtOAc, 4:1–2:1) to afford
4a as a colorless solid; yield: 1.4 g (99%).
p-Methoxybenzyl 3-(3,5-Dimethyl-4-methoxyphenylthio)meth-
yl-7-phenylacetamido-D3-cephem-4-carboxylate (4d)
Reaction of 2 (1.0 g, 2.1 mmol), 4-methoxy-3,5-dimethylben-
zenethiol (5d) (0.42 g, 2.5 mmol) and KHCO3 (0.42 g, 4.2 mmol) in
acetone (10 mL) and H2O (1.5 mL) afforded 4d as a colorless solid;
yield: 1.2 g (95%).
IR (Nujol): 3259, 1778, 1715, 1656, 1630, 1614, 1537, 1517 cm–1.
IR (KBr): 2969, 2362, 1781, 1684, 1613, 1516, 1247 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.37 (s, 18 H), 3.34 (d, J = 18 Hz,
1 H), 3.52 (d, J = 18 Hz, 1 H), 3.59 (s, 2 H), 3.63 (s, 3 H), 3.74 (d,
1H NMR (200 MHz, CDCl3): d = 2.20 (s, 6 H), 3.32 (d, J = 18 Hz,
1 H), 3.56 (d, J = 18 Hz, 1 H), 3.63 (s, 2 H), 3.67 (s, 3 H), 3.73 (d,
J = 14 Hz, 1 H), 3.79 (s, 3 H), 4.10 (d, J = 14 Hz, 1 H), 4.84 (d, J = 6
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

PAPER
Electrooxidation of 3-(Arylthiomethyl)-D3-cephems
3457
Hz, 1 H), 4.99 (d, J = 12 Hz, 1 H), 5.10 (d, J = 12 Hz, 1 H), 5.73
(dd, J = 8, 4 Hz, 1 H), 6.09 (d, J = 6 Hz, 1 H), 6.86 (d, J = 8 Hz, 2
H), 6.99 (s, 2 H), 6.25–7.39 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 16.00, 28.35, 38.02, 43.32, 55.23,
57.66, 59.01, 59.70, 67.68, 113.89, 124.18, 126.78, 127.08, 127.69,
128.16, 129.15, 129.42, 129.75, 130.49, 131.74, 133.65, 156.97,
159.80, 161.31, 164.40, 171.08.
13C NMR (75 MHz, CDCl3): d = 28.35, 37.48, 43.19, 55.24, 57.77,
59.03, 67.68, 113.91, 124.24, 126.82, 127.50, 127.66, 128.30,
128.99, 129.36, 129.48, 130.58, 132.10, 133.90, 134.06, 159.83,
161.38, 164.56, 171.22.
Anal. Calcd for C30H28N2O5S2: C, 64.27; H, 5.03; N, 5.00. Found:
C, 64.01; H, 4.82; N, 4.81.
1,3-Di-tert-butyl-2-methoxy-5-(methylsulfanyl)benzene (11);
Typical Procedure
Anal. Calcd for C33H34N2O6S2: C, 64.06; H, 5.54; N, 4.53. Found:
C, 63.88; H, 5.49; N, 4.31.
To a mixture of 3,5-di-tert-butyl-4-methoxybenzenethiol (5a) (1.2
g, 4.8 mmol) and NaH (0.5 g, 8.3 mmol) in DMF (10 mL) was add-
ed MeI (0.5 mL, 8.1 mmol) under an Ar atm. The reaction mixture
was stirred at r.t. for 1.5 h and then diluted with EtOAc (50 mL),
washed with 5% aq HCl (10 mL) and brine (3 × 10 mL), and then
dried over Na2SO4. The solvent was removed under reduced pres-
sure and the residue was purified by silica gel chromatography (elu-
ent: hexane) to afford 11 as a pale-yellow oil; yield: 0.94 g (74%).
IR (neat): 2962, 2870, 1575, 1409, 1360, 1258 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.42 (s, 18 H), 2.45 (s, 3 H), 3.66
(s, 3 H), 7.18 (s, 2 H).
p-Methoxybenzyl 3-(4-Methoxyphenylthio)methyl-7-phenyl-
acetamido-D3-cephem-4-carboxylate (4e)
Reaction of 2 (1.0 g, 2.1 mmol), 4-methoxybenzenethiol (5e) (0.35
g, 2.5 mmol) and KHCO3 (0.42 g, 4.2 mmol) in acetone (10 mL) and
H2O (1.5 mL) afforded 4e as a colorless solid; yield: 1.2 g (94%).
IR (Nujol): 3293, 3032, 1770, 1716, 1660, 1613, 1593, 1571 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.26 (d, J = 18 Hz, 1 H), 3.57 (d,
J = 14 Hz, 1 H), 3.61 (d, J = 18 Hz, 1 H), 3.61 (s, 2 H), 3.74 (s, 3
H), 3.80 (s, 3 H), 4.26 (d, J = 14 Hz, 1 H), 4.81 (d, J = 5 Hz, 1 H),
4.90 (d, J = 11 Hz, 1 H), 5.02 (d, J = 11 Hz, 1 H), 5.71 (dd, J = 8, 5
Hz, 1 H), 6.24 (d, J = 8 Hz, 1 H), 6.75 (d, J = 8 Hz, 2 H), 6.87 (d,
J = 8 Hz, 2 H), 6.30–7.40 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 16.96, 31.92, 35.82, 64.17, 125.99,
130.99, 144.18, 157.73.
13C NMR (75 MHz, CDCl3): d = 28.42, 38.82, 43.31, 55.25, 57.65,
59.01, 67.63, 113.87, 114.58, 123.94, 124.07, 126.83, 127.66,
129.12, 129.42, 129.63, 130.56, 133.68, 135.46, 159.81, 159.85,
161.29, 164.33, 171.05.
Anal. Calcd for C16H26OS: C, 72.13; H, 9.84. Found: C, 72.18; H,
9.71.
2,6-Di-tert-butyl-4-(methylsulfanyl)phenol (12)
Reaction of 2,6-di-tert-butyl-4-sulfanylphenol (5b) (1.5 g, 6.3
mmol), NaH (0.8 g, 13 mmol) and MeI (0.6 mL, 9.7 mmol) in DMF
(10 mL) at r.t. under an Ar atm for 1.5 h afforded 12 as a pale-yellow
oil; yield: 0.95 g (60%).
Anal. Calcd for C31H30N2O6S2: C, 63.03; H, 5.12; N, 4.74. Found:
C, 63.01; H, 5.20; N, 4.63.
p-Methoxybenzyl 3-(4-Methylphenylthio)methyl-7-phenyl-
acetamido-D3-cephem-4-carboxylate (4f)
IR (neat): 3640, 2961, 1581, 1425, 1304, 1234, 1156 cm–1.
Reaction of 2 (1.0 g, 2.1 mmol), 4-methylbenzenethiol (5f) (0.35 g,
2.5 mmol) and KHCO3 (0.42 g, 4.2 mmol) in acetone (10 mL) and
H2O (1.5 mL) afforded 4f as a colorless solid; yield: 1.2 g (95%).
IR (Nujol): 3295, 1778, 1718, 1655, 1633, 1616, 1585, 1533 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.43 (s, 18 H), 2.45 (s, 3 H), 5.15
(s, 1 H), 7.19 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.34, 30.14, 34.44, 126.14,
126.97, 136.65, 152.54.
1H NMR (200 MHz, CDCl3): d = 2.29 (s, 3 H), 3.29 (d, J = 18 Hz,
1 H), 3.60 (d, J = 18 Hz, 1 H), 3.61 (d, J = 14 Hz, 1 H), 3.64 (d,
J = 14 Hz, 1 H), 3.65 (d, J = 14 Hz, 1 H), 3.80 (s, 3 H), 4.26 (d,
J = 14 Hz, 1 H), 4.82 (d, J = 6 Hz, 1 H), 5.00 (d, J = 12 Hz, 1 H),
5.07 (d, J = 12 Hz, 1 H), 5.72 (dd, J = 9, 6 Hz, 1 H), 6.03 (d, J = 9
Hz, 1 H), 6.87 (d, J = 9 Hz, 2 H), 7.02 (d, J = 9 Hz, 2 H), 7.18–7.40
(m, 9 H).
13C NMR (75 MHz, CDCl3): d = 21.09, 28.35, 36.92, 43.29, 55.24,
57.62, 58.89, 67.63, 113.89, 124.16, 126.83, 127.66, 129.12,
129.33, 129.41, 129.78, 130.24, 130.52, 132.58, 133.65, 137.90,
159.82, 161.34, 164.35, 171.03.
Anal. Calcd for C15H24OS: C, 71.38; H, 9.58. Found: C, 71.28; H,
9.77.
Electrooxidation of p-Methoxybenzyl 3-(3,5-Di-tert-butyl-4-
methoxyphenyl)thiomethyl-7-phenylacetamido-D3-cephem-4-
carboxylate (4a) (Table 1, Entry 6); Typical Procedure
Electrolysis was carried out in a beaker-type undivided cell contain-
ing two Pt electrodes (1.0 × 1.5 cm2). A mixture of 4a (150 mg, 0.21
mmol), Bu4NBF4 (50 mg), MgSO4 (50 mg), and TFE (0.05 mL) in
CH2Cl2 (2.8 mL) and MeOH (0.2 mL) was subjected to a constant
current density (10 mA/cm2) under an N2 atm at 0–5 °C. After pas-
sage of 5.0 F/mol of electricity, the mixture was concentrated and
the residue was diluted with EtOAc (15 mL), washed with brine
(3 × 5 mL), dried (Na2SO4) and evaporated under reduced pressure.
The residue was chromatographed over silica gel (eluent: hexane–
EtOAc, 10:1–1:1) to afford compounds 3 (3a:3b:3c = 80:2:18);
combined yield: 84 mg (84%), 7, 8 and 9. Electrooxidation of com-
pounds 4c–g was carried out in a similar manner and the results are
summarized in Table 3.
Anal. Calcd for C31H30N2O5S2: C, 64.76; H, 5.26; N, 4.87. Found:
C, 64.57; H, 5.19; N, 4.56.
p-Methoxybenzyl 7-Phenylacetamido-3-phenylthiomethyl-D3-
cephem-4-carboxylate (4g)
Reaction of cephem 2 (1.0 g, 2.1 mmol), benzenethiol 5g (0.33 g,
3.0 mmol) and KHCO3 (0.40 g, 4.0 mmol) in acetone (10 mL) and
H2O (1.5 mL) afforded 4g as a colorless solid; yield: 1.1 g (95%).
IR (KBr): 3278, 1781, 1720, 1684, 1616, 1515 cm–1.
p-Methoxybenzyl 3-Methoxymethyl-7-phenylacetamido-D3-
cephem-4-carboxylate (3a)
Colorless solid.
1H NMR (200 MHz, CDCl3): d = 3.28 (d, J = 18 Hz, 1 H), 3.59 (d,
J = 18 Hz, 1 H), 3.61 (d, J = 16 Hz, 1 H), 3.64 (d, J = 16 Hz, 1 H),
3.70 (d, J = 14 Hz, 1 H), 3.80 (s, 3 H), 4.27 (d, J = 14 Hz, 1 H), 4.81
(d, J = 5 Hz, 1 H), 5.01 (d, J = 12 Hz, 1 H), 5.07 (d, J = 12 Hz, 1 H),
5.72 (dd, J = 9, 5 Hz, 1 H), 6.12 (d, J = 9 Hz, 1 H), 6.87 (d, J = 9
Hz, 2 H), 7.20–7.37 (m, 12 H).
IR (KBr): 3260, 1776, 1712, 1653, 1539, 1517 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.26 (s, 3 H), 3.45 (s, 2 H), 3.62
(d, J = 12 Hz, 1 H), 3.65 (d, J = 12 Hz, 1 H), 3.80 (s, 3 H), 4.24 (s,
2 H), 4.91 (d, J = 4 Hz, 1 H), 5.18 (s, 2 H), 5.80 (dd, J = 6, 4 Hz, 1
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H. Tanaka et al.
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H), 6.04 (d, J = 6 Hz, 1 H), 6.87 (d, J = 6 Hz, 2 H), 7.22–7.39 (m, 7
H).
1H NMR (200 MHz, CDCl3): d = 1.37 (s, 36 H), 3.66 (s, 6 H), 7.39
(s, 4 H).
13C NMR (75 MHz, CDCl3): d = 25.93, 43.19, 55.23, 57.57, 58.27,
59.12, 67.81, 70.49, 113.93, 124.19, 126.83, 127.56, 129.05,
129.38, 129.47, 130.58, 133.83, 159.85, 161.55, 164.88, 171.23.
13C NMR (75 MHz, CDCl3): d = 34.73, 38.76, 67.12, 130.35,
133.79, 147.34, 162.23.
Anal. Calcd for C30H46O2S2: C, 71.66; H, 9.22. Found: C, 71.41; H,
9.02.
Anal. Calcd for C25H26N2O6S: C, 62.23; H, 5.43; N, 5.81. Found: C,
62.53; H, 5.43; N, 5.82.
Methyl 3,5-Di-tert-butyl-4-methoxybenzenesulfinate (9)
Colorless solid; yield: 50 mg (78%).
IR (KBr): 3020, 1449, 1406, 1224, 1113 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.45 (s, 18 H), 3.53 (s, 3 H), 3.72
(s, 3 H), 7.58 (s, 2 H).
p-Methoxybenzyl 3-Methoxymethyl-7-phenylacetamido-D2-
cephem-4-carboxylate (3b)
Colorless solid.
IR (KBr): 3299, 1769, 1735, 1658, 1615, 1530 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.17 (s, 3 H), 3.62 (d, J = 11 Hz,
1 H), 3.64 (d, J = 11 Hz, 1 H), 3.78 (d, J = 8 Hz, 1 H), 3.80 (s, 3 H),
3.93 (d, J = 8 Hz, 1 H), 4.96 (s, 1 H), 5.08 (d, J = 8 Hz, 1 H), 5.12
(d, J = 8 Hz, 1 H), 5.21 (d, J = 4 Hz, 1 H), 5.62 (dd, J = 6, 4 Hz, 1
H), 6.12 (d, J = 6 Hz, 1 H), 6.22 (s, 1 H), 6.89 (d, J = 6 Hz, 2 H),
7.24–7.39 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 43.35, 50.09, 53.55, 55.30, 57.89,
60.19, 67.77, 73.97, 114.09, 118.66, 121.50, 126.80, 127.69,
129.14, 129.49, 130.34, 133.65, 159.97, 164.34, 167.23, 170.93.
13C NMR (75 MHz, CDCl3): d = 30.42, 34.76, 48.71, 63.13, 122.10,
136.14, 143.78, 161.54.
Anal. Calcd for C16H26O3S: C, 64.39; H, 8.78. Found: C, 64.64; H,
8.68.
Electrooxidation of p-Methoxybenzyl 3-(3,5-Di-tert-butyl-4-
hydroxyphenyl)thiomethyl-7-phenylacetamido-D3-cephem-4-
carboxylate (4b) (Table 2, Entry ); Typical Procedure
Electrolysis of 4b was carried out in a beaker-type undivided cell
containing two Pt electrodes (1.0 × 1.5 cm2). A mixture of 4b (150
mg, 0.19 mmol) and Et4NClO4 (50 mg) in MeCN (5.0 mL) and
MeOH (1.0 mL) was electrolyzed under a constant current density
(10 mA/ cm2) at r.t. under an N2 atm. After passage of 4.0 F/mol of
electricity for 1.3 h, the mixture was concentrated under reduced
pressure. The residue was diluted with EtOAc (15 mL), washed
with brine (3 × 5 mL), dried (Na2SO4) and concentrated under re-
duced pressure. The residue was chromatographed over silica gel
(hexane–EtOAc, 5:1–1:1) to afford disulfide 6 and 2,6-di-tert-
butyl-4,4-dimethoxycyclohexa-2,5-dien-1-one (10). Additional re-
sults obtained by variation of the conditions are summarized in
Table 2.
Anal. Calcd for C25H26N2O6S: C, 62.23; H, 5.43; N, 5.81. Found: C,
62.35; H, 5.48; N, 5.93.
p-Methoxybenzyl 3-exo-Methylene-4-methoxy-7-phenylacet-
amidocepham-4-carboxylate (3c)
Colorless solid.
IR (Nujol): 3560, 3453, 3264, 3199, 3061, 1785, 1725, 1657, 1615,
1585, 1556 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.24 (d, J = 12 Hz, 1 H), 3.46 (d,
J = 12 Hz, 1 H), 3.43 (s, 3 H), 3.63 (s, 2 H), 3.81 (s, 3 H), 4.99 (d,
J = 3 Hz, 1 H), 5.07 (d, J = 12 Hz, 1 H), 5.23 (d, J = 12 Hz, 1 H),
5.34 (s, 1 H), 5.48 (dd, J = 9, 3 Hz, 1 H), 5.50 (s, 1 H), 6.45 (d, J = 9
Hz, 1 H), 6.88 (d, J = 9 Hz, 2 H), 7.24–7.38 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 28.88, 43.32, 53.18, 54.92, 55.26,
59.85, 68.41, 86.09, 113.94, 118.36, 126.76, 127.47, 128.94,
129.48, 130.36, 133.88, 137.15, 159.85, 164.32, 165.10, 170.99.
Bis[(4-p-methoxybenzyloxycarbonyl-7-phenylacetamido-D3-
cephem-3-yl)methyl] Disulfide (6)
Colorless solid; yield: 82 mg (90%).
IR (KBr): 3286, 2999, 1774, 1712, 1685, 1516, 1248, 1159, 1098
cm–1.
HRMS (FAB): m/z calcd for C25H27N2O6S (M + H)+: 483.1588;
1H NMR (200 MHz, CDCl3): d = 3.41 (d, J = 18 Hz, 2 H), 3.53 (d,
J = 14 Hz, 2 H), 3.54 (d, J = 18 Hz, 2 H), 3.61 (s, 4 H), 3.76 (d,
J = 14 Hz, 2 H), 3.77 (s, 6 H), 4.89 (d, J = 5 Hz, 2 H), 5.14 (d, J = 11
Hz, 2 H), 5.20 (d, J = 11 Hz, 2 H), 5.82 (dd, J = 10, 5 Hz, 2 H), 6.68
(d, J = 10 Hz, 2 H), 6.85 (d, J = 9 Hz, 4 H), 7.26–7.34 (m, 14 H).
found: 483.1609.
p-Methoxybenzyl 3-Dimethoxymethyl-7-phenylacetamido-D3-
cephem-4-carboxylate (7)
Colorless solid; yield: 5 mg (5%).
13C NMR (75 MHz, CDCl3): d = 28.52, 42.81, 50.27, 52.42, 55.17,
58.73, 60.37, 67.88, 114.33, 122.58, 127.05, 127.66, 128.78,
129.71, 130.55, 131.01, 160.24, 162.44, 166.02, 171.62.
IR (Nujol): 3294, 3271, 1775, 1731, 1713, 1659, 1612, 1590, 1531,
1517 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.24 (s, 3 H), 3.37 (s, 3 H), 3.39
(d, J = 18 Hz, 1 H), 3.57 (d, J = 18 Hz, 1 H), 3.64 (d, J = 4 Hz, 1 H),
3.65 (d, J = 4 Hz, 1 H), 3.80 (s, 3 H), 4.91 (d, J = 4 Hz, 1 H), 5.18
(d, J = 12 Hz, 1 H), 5.22 (d, J = 12 Hz, 1 H), 5.27 (s, 1 H), 5.82 (dd,
J = 9, 5 Hz, 1 H), 6.00 (d, J = 9 Hz, 1 H), 6.89 (d, J = 8 Hz, 2 H),
7.22–7.42 (m, 7 H).
Anal. Calcd for C48H46N4O10S4: C, 59.61; H, 4.79; N, 5.79. Found:
C, 59.70; H, 4.75; N, 5.69.
2,6-Di-tert-butyl-4,4-dimethoxycyclohexa-2,5-dien-1-one (10)
Colorless solid; yield: 46 mg (91%).
13C NMR (75 MHz, CDCl3): d = 22.68, 43.31, 55.11, 55.64, 57.90,
59.11, 69.09, 101.42, 113.97, 125.31, 126.68, 127.71, 127.75,
129.21, 129.29, 130.75, 133.58, 159.97, 161.44, 165.03, 171.08.
IR (KBr): 3644, 2962, 2361, 1655, 1425, 1216, 1064 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.43 (s, 18 H), 3.77 (s, 6 H), 6.76
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 29.38, 35.59, 55.61, 130.17,
157.89, 187.77, 189.14.
Anal. Calcd for C26H28N2O7S: C, 60.92; H, 5.51; N, 5.47. Found: C,
60.91; H, 5.35; N, 5.08.
Bis(3,5-di-tert-butyl-4-methoxyphenyl) Disulfide (8)
Colorless solid; yield: 9 mg (9%).
Anal. Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C, 72.31; H,
9.87.
IR (KBr): 3015, 2963, 1570, 1447, 1407, 1222 cm–1.
Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York

PAPER
Electrooxidation of 3-(Arylthiomethyl)-D3-cephems
3459
Cyclic Voltammetry on Compounds 4a,b,d,g, 11 and 12
A soln of the sulfide derivative (1.6 × 10–3 M) in MeCN containing
Bu4NBF4 (0.3 M) was added to a three-electrode cell containing a
Pt disk (0.2 cm2) as the working electrode, a Pt wire (ca. 1 cm2 ap-
parent surface) as the auxiliary electrode and a saturated calomel
electrode as the reference electrode. The potential was swept at a
rate of 200 mV/s until the electrode current became limited (ca. –0.3
to +2.3 V).
Kamada, A.; Tsuda, I.; Hiruma, R.; Katsu, K.; Machida, Y.
J. Antibiot. 1994, 47, 1507.
(4) Topics in Antibiotics Chemistry, Vol. 4; Sammes, P. G., Ed.;
Ellis Horwood: Chichester, 1980.
(5) Cefpodoxime proxetil, bearing a methoxymethyl moiety at
the C-3 position of cephalosporin derivatives, has been used
as an orally active drug. Its precursor, 3-methoxymethyl-D3-
cephem was prepared by methoxylation of the correspond-
ing 3-acetoxymethyl-D3-cephem derivative using CaCl2 in
aq MeOH, see: Fujimoto, K.; Ishihara, S.; Yanagisawa, H.;
Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.
J. Antibiot. 1987, 40, 370.
Acknowledgment
We acknowledge financial support by Grants-in-Aid for Scientific
Research (06453140 and 05403025) from the Ministry of Educa-
tion, Science, and Culture of Japan. The SC-NMR Laboratory of
Okayama University is thanked for recording NMR spectra.
(6) (a) Recent Advances in the Chemistry of b-Lactam
Antibiotics, Special Publication No. 38; Gregory, G. I., Ed.;
The Royal Society of Chemistry: London, 1980.
(b) Webber, J. A.; Huffman, G. W.; Koehler, R. E.; Murphy,
C. F.; Ryan, C. W.; Van Heyningen, E. M.; Vasileff, R. T.
J. Med. Chem. 1971, 14, 113. (c) Animati, F.; Botta, M.;
De Angelis, F.; Dorigo, A.; Grgurina, I.; Nicoletti, R.
J. Chem. Soc., Perkin Trans. 1 1983, 2281. (d)Koyama, Y.;
Huang, S.-P.; Keda, D.; Kondo, S. Synlett 1990, 389.
(7) GCLE® is commercially available from Otsuka Chemical
Co., Ltd., see: Taniguchi, M.; Misawa, T.; Shiroi, T.; Torii,
S.; Tanaka, H. Nippon Kagaku Kaishi 1995, 577.
(8) For a report on non-electrochemical oxidation and nucleo-
philic substitution of 2-(ceph-3-em-3-ylmethylthio)pyridine
N-oxide with CuCl2 in MeOH, see: Ochiai, M.; Aki, O.;
Morimoto, A.; Okada, T.; Kaneko, T. Tetrahedron Lett.
1972, 23, 2345.
(9) (a) Prasada, R.; Korrapati, V. V.; Dandala, R.; Handa, V. K.;
Subramanyeswara, K.; Anand, G.; Rao, I. V.; Rani, A.;
Naidu, A. J. Heterocycl. Chem. 2007, 44, 1513. (b) Sendo,
Y.; Yoshioka, M.; Nagata, W. Heterocycles 1982, 17, 231.
(10) Isomerization of 3-exo-methylene-4-methoxycepham 3c
into 3-methoxymethyl-D3-cephem 3a was accomplished in
MeOH containing HCl.8
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Synthesis 2009, No. 20, 3449–3459 © Thieme Stuttgart · New York